SUMMARY One in five people suffer from some form of functional gastrointestinal and motility disorders (FGIMD), a group of diseases caused by malfunction of the enteric (gut) nervous system (ENS), including irritable bowel syndrome, fecal incontinence, constipation, dyspepsia, and others. Pharmaceutical intervention is largely unsuccessful at managing these conditions. Recently, electrical sacral nerve stimulation (SNS) has emerged as an alternative therapy for FGIMD. However, how the sacral nerves innervate and modulate the ENS is unknown, so clinicians have to resort to one set of empirical stimulation parameters in hopes of relieving different (sometimes opposite) conditions, with very inconsistent outcomes. The objective of this project is to understanding how the sacral nerves innervate and modulate the enteric nervous system. We pose three hypothetical mechanisms through which SNS modulates gut motility: SNS modulates [a] enteric neurons, [b] smooth muscle, and / or [c] intrinsic pacemaker cells. The challenge is that there is no specific tool, such as pharmacological blockers, transgenic animal models, etc., that can distinguish these three hypothetical mechanisms in vivo. To overcome this challenge, we will build the first computational model that integrates the sacral nerves, the ENS, and GI motility. For each hypothetic mechanism, the in silico framework will predict distinct neuron and muscle firing patterns, which can then be experimentally validated in vivo by c-Fos+ immunomapping and intravital colon imaging. The in silico framework will also predict motility patterns during SNS, which will be validated by implantable motility sensors in awake animals. Once the fundamental mechanism of the SNS-ENS interface is understood, we will use the improved in silico model to optimize SNS parameters that maximally increase or decrease colonic motility, followed by in vivo validation. In summary, we will combine computational modeling and in vivo experiments to determine how the sacral nerves innervate and modulate the ENS and GI motility. Our model will provide fundamental understanding of how peripheral nerves interface with an organ, which is generalizable to other types of peripheral nerves such as the vagus nerve. The model will also enable us to test the hypothesis that specific stimulation patterns can be delivered to treat different conditions in the lower GI system, rather than using the current one-size-fits-all, hit-or-miss approach.